Region of the small bowel over-represented in NF1-mutated GISTs

Paul Basilio, MDLinx | August 22, 2017

Researchers at UC San Diego Moores Cancer Center, Memorial Sloan Kettering Cancer Center, and Fox Chase Cancer Center have found that the duodenal-jejunal flexure (DJF) is a flashpoint of gastrointestinal stromal tumors (GISTs) with mutations of the NF1 gene. The findings were published online in JCO Precision Oncology.

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Genomic testing revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1.

Approximately 30% of all GISTs occur in the small bowel, which is divided into three anatomically, histologically, and functionally distinct segments: the duodenum, jejunum and ileum. Most small bowel GISTs are associated with KIT mutations; however, a subset of GISTs have mutations in other genes, such as NF1.

“Where the duodenum transitions into the jejunum, we are finding an over-representation of NF1-mutated GIST,” said Jason Sicklick, MD, Surgical Oncologist at Moores Cancer Center.

Mutations in NF1 occur both somatically (within tumor DNA) or in the germline (part of the hereditary condition called Neurofibromatosis type 1 [NF-1]). Patients with NF-1 are 34 times more likely to have GISTs when compared with unaffected individuals.

“Genomic testing for some of these patients revealed occult germline NF1 mutations with no other obvious clinical symptoms of NF-1,” Dr. Sicklick said. “Anyone with a GIST should undergo tumor genetic testing. Currently only 8% to 15% of patients get tested. For those patients with NF1 mutations, there are implications for family members of patients who test positive for hereditary NF-1, as they also may be at increased risk of developing cancers, including GIST.”

NF-1 occurs in one in 3,000 to 4,000 individuals worldwide. It is characterized by changes in skin coloring and the growth of tumors along nerves in the skin, brain, and other parts of the body, such as the GI tract. Signs and symptoms can vary widely among patients.

GIST represents the most common type of sarcoma in the GI tract, with an annual incidence of 6.8 cases per million people in the US. These tumors start in the interstitial cells of Cajal (ICCs), which are sometimes called the “pacemakers” of the GI tract because they signal the muscles in the digestive system to contract through peristalsis.

Dr. Sicklick and colleagues at Moores Cancer Center are currently searching for a personalized approach to GIST tumors that become progressively resistant to treatment. Ultimately, more than 95% of patients with drug-resistant GISTs die from the disease.

“Patients with GIST should have their tumors profiled with next-generation sequencing panels,” said Adam Burgoyne, MD, PhD, first author of the study and Medical Oncologist at Moores. “We are uncovering a subset of patients, including patients with mutations of KIT, who have downstream mutations that may render them insensitive to conventional targeted therapy.”

Dr. Sicklick added that this insight helps physicians to know which drugs will or won’t work to help them properly treat these deadly tumors.

“Of critical importance in NF1 mutant GIST,” he added, “standard-of-care drug regimens aren’t effective.”

Dr. Sicklick’s recent GIST research has also identified new gene fusions and mutations associated with subsets of GIST patients. He and his team also provided the first evidence that the Hedgehog signaling pathway is central to the formation of GIST, which are frequently driven by the KIT oncogene.

To read more about this study, click here

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